Although Sickle Cell Anemia (SCA) has been characterized at the molecular level, the pathophysiology of its protein manifestation the vasocclusive crisis (VOC) still remains obscure. The exact events that lead to microcirculatory impairment and obstruction by sickled erythrocytes involve a complex and dynamic sequence of events that dependent presumably as much on microcirculatory tone, the activation state of the endothelium, white cells, platelets, and the fluid phases of coagulation as it does on the surface and internal characteristics of the red cell and its content of sickle and fetal hemoglobin. This Center grant will attempt to address the areas enumerated above in a unique and prospective fashion with focus on the crucial window of time during which a watershed change occurs in the erythrocyte's internal characteristics i.e.-its hemoglobin content of S and F. We will meticulously correlate how these physiologic changes in hemoglobin content during the first few years of life will affect the state of activation of the other cellular elements of blood, coagulation factors and endothelium, and how these changes effect the protein clinical manifestations of the disease-VOC and the occurrence of pain. The incidence and the attributes of sickle pain in these infants and young children will be assessed in a comprehensive and prospective longitudinal study. Additionally, our research program will explore at the cellular and molecular level the rationale for potential use of interventional strategies directed at one of the life threatening complications of Sickle Cell Disease, the acute chest syndrome, and also investigate a second and interventional program designed for our children in late childhood and early adolescence which will increase their resilience and perceived control over their lives and illness. Thus, this Center Grant seeks to address various aspect of basic and translational research besides providing the support our patients require to lead independent and productive lives. The research projects will be supported by the traditional aspects of a Comprehensive Sickle Cell Center including education and counseling services, a diagnostic and laboratory core, and appropriate statistical and administrative support.